In recent years our research findings have provided a new appreciation for the potential pharmacological properties of cotinine, the principal metabolite of nicotine produced after using tobacco products. We now provide compelling evidence that cotinine is indeed a pharmacologically active compound having a number of actions that suggest that it might mediate some of the beneficial effects of nicotine, as well as exhibiting some unique properties of its own. Cotinine was shown to have full efficacy (relative to nicotine) in protecting neural-like cells in culture from a cytotoxic insult. The drug was active in a rat model that predicts antipsychotic-like potential. Cotinine also improved working memory accuracy by non-human primates, and the drug exhibited ability to enhance attention in a distractor version of the same task. Finally we demonstrated that unlike nicotine, cotinine failed to stimulate autonomic ganglionic transmission in the awake rat, but it partly desensitized ganglionic receptors without affecting resting blood pressure. We propose to extend these findings by studying the potential neuroprotective properties of cotinine in a transgenic mouse model of Alzheimer's disease. The potential of cotinine as a prototypical agent to improve cognition in schizophrenia will be studied in a rat model of sustained attention and in monkeys in a working memory task by evaluating the ability of the compound to attenuate or reverse the impairing effects of low doses of psychotomimetic agents. Finally, the relative ability of cotinine to desensitize nicotinic receptors will be determined in of acetylcholine release from relevant regions of rat and monkey CNS. We expect at the completion of these studies to show that cotinine has exploitable therapeutic potential relevant to human diseases that feature behavioral and cognitive impairment and neurodegeneration. Based on its cognition-enhancing and antipsychotic potential, cotinine also could prove useful in the difficult to treat cognitive deficits associated with schizophrenia. Perhaps even more importantly cotinine has the potential to serve as a prototypical agent by which new drug entities may be compared. The partly translational design of the study will provide results leading to eventual clinical trials with cotinine or a relevant analog. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG029617-01A1
Application #
7319309
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Buckholtz, Neil
Project Start
2007-09-01
Project End
2011-06-30
Budget Start
2007-09-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$301,350
Indirect Cost
Name
Georgia Regents University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Terry Jr, Alvin V; Callahan, Patrick M; Hernandez, Caterina M (2015) Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders. Biochem Pharmacol 97:388-398
Li, Pei; Beck, Wayne D; Callahan, Patrick M et al. (2015) Pharmacokinetics of cotinine in rats: a potential therapeutic agent for disorders of cognitive function. Pharmacol Rep 67:494-500
Terry Jr, Alvin V; Callahan, Patrick M; Bertrand, Daniel (2015) R-(+) and S-(-) isomers of cotinine augment cholinergic responses in vitro and in vivo. J Pharmacol Exp Ther 352:405-18
Gao, Jie; Adam, Bao-Ling; Terry Jr, Alvin V (2014) Evaluation of nicotine and cotinine analogs as potential neuroprotective agents for Alzheimer's disease. Bioorg Med Chem Lett 24:1472-8
Callahan, Patrick M; Hutchings, Elizabeth J; Kille, Nancy J et al. (2013) Positive allosteric modulator of *7 nicotinic-acetylcholine receptors, PNU-120596 augments the effects of donepezil on learning and memory in aged rodents and non-human primates. Neuropharmacology 67:201-12
Wilson, Christina A; Terry Jr, Alvin V (2013) Variable maternal stress in rats alters locomotor activity, social behavior, and recognition memory in the adult offspring. Pharmacol Biochem Behav 104:47-61
Wilson, Christina A; Vazdarjanova, Almira; Terry Jr, Alvin V (2013) Exposure to variable prenatal stress in rats: effects on anxiety-related behaviors, innate and contextual fear, and fear extinction. Behav Brain Res 238:279-88
Wilson, C A; Schade, R; Terry Jr, A V (2012) Variable prenatal stress results in impairments of sustained attention and inhibitory response control in a 5-choice serial reaction time task in rats. Neuroscience 218:126-37
Terry Jr, A V (2012) Functional consequences of repeated organophosphate exposure: potential non-cholinergic mechanisms. Pharmacol Ther 134:355-65
Li, Pei; Beck, Wayne D; Callahan, Patrick M et al. (2012) Quantitation of cotinine and its metabolites in rat plasma and brain tissue by hydrophilic interaction chromatography tandem mass spectrometry (HILIC-MS/MS). J Chromatogr B Analyt Technol Biomed Life Sci 907:117-25

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